WO2019214749A1 - Procédé de synthèse d'un dérivé de benzofurane au moyen d'un acide de lewis non métallique catalysant l'addition d'une liaison c-o à l'intérieur d'une molécule d'oléfine - Google Patents

Procédé de synthèse d'un dérivé de benzofurane au moyen d'un acide de lewis non métallique catalysant l'addition d'une liaison c-o à l'intérieur d'une molécule d'oléfine Download PDF

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WO2019214749A1
WO2019214749A1 PCT/CN2019/087153 CN2019087153W WO2019214749A1 WO 2019214749 A1 WO2019214749 A1 WO 2019214749A1 CN 2019087153 W CN2019087153 W CN 2019087153W WO 2019214749 A1 WO2019214749 A1 WO 2019214749A1
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Prior art keywords
olefin
lewis acid
reaction
bond
derivative
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PCT/CN2019/087153
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English (en)
Chinese (zh)
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赵继阳
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南京晓庄学院
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Publication of WO2019214749A1 publication Critical patent/WO2019214749A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a benzofuran derivative.
  • Benzofuran compounds are a class of natural organic compounds widely found in plants, such as in medicinal plants such as Salvia miltiorrhiza, Hundreds, Wild Jasmine, and Zanthoxylum bungeanum. Benzofuran compounds have good antibacterial, anti-oxidative, anti-tumor, anti-viral and other physiological activities, and thus can be used for selective adenosine A1 receptor antagonists, immunosuppressive agents and the like. However, since the extraction of benzofuran compounds from natural products cannot meet people's needs, it is very important to obtain them by artificial synthesis.
  • Olefin addition reactions are a very important class of chemical conversion reactions in organic synthesis and medicinal chemistry.
  • Direct addition of C-O bonds to olefins is a very cost effective olefin functionalization process for both atoms and steps.
  • olefin addition C-X (X is a hetero atom) has gained wide attention, the direct addition of C-O bonds to olefins is still challenging due to the high stability of C-O bonds.
  • the Nakao team used synergistic metal palladium and boric acid catalysts to achieve intramolecular addition of C-O bonds to olefins to give benzofurans. The reaction was carried out in a solvent of 80 ° C in tetrahydrofuran.
  • the present invention adopts the following technical solutions:
  • a method for synthesizing a benzofuran derivative by intramolecular addition of a C-O bond to an olefin by a non-metal Lewis acid comprising the steps of:
  • Step one preparing an olefin: using a phenol derivative as a raw material, and passing through a three-step reaction as shown in the following reaction formula, an olefin as a reaction substrate is obtained; the reaction formula is as follows:
  • R is H or OMe
  • Step 2 adding the non-metal Lewis acid and toluene to the olefin prepared in the first step, and reacting to obtain the benzofuran derivative; the reaction formula is as follows:
  • the first step is specifically: adding potassium carbonate, methallyl chloride and compound 1 to the stirring acetone solution, and refluxing the formed mixture at room temperature overnight, then adding water, and extracting with diethyl ether to collect the organic layer. and washed with NaOH, dried over MgSO 4 performed, filtered and concentrated in vacuo to give the intermediate compound 2; intermediate compound 2 was dissolved in N, N- dimethylaniline or N, N- dimethylformamide, and the mixture at 200 Reflux in a nitrogen atmosphere at -250 ° C for 1-5 hours, then cool to room temperature, and concentrate under reduced pressure.
  • the solvent was a mixture of anhydrous hexane and diethyl ether in a volume ratio of 5:2.
  • the olefin, the non-metal Lewis acid and the toluene prepared in the first step are mixed and placed in a closed vessel and reacted at 90 ° C for 12-24 hours; after the reaction is completed, it is cooled to room temperature and diluted with diethyl ether; finally concentrated with diatomaceous earth.
  • the product was purified by column chromatography and dried to give the product.
  • the non-metallic Lewis acid is B(C 6 F 5 ) 3 .
  • a non-metallic Lewis acid is used as a catalyst in the reaction, and the electrons in the O-C bond are extracted by the complexation of the Lewis acid with the cyano group in the reaction substrate, thereby weakening the chemical bond strength of the O-C bond.
  • This mode of activation of the Lewis acid is different from that of the transition metal, but achieves the same effect as the transition metal.
  • contamination of the reaction system by the metal catalyst is avoided, and troublesome post-treatment is also eliminated.
  • Example 1 is an H NMR spectrum of a raw material olefin obtained in Example 1;
  • Example 2 is a 13 C NMR spectrum of the raw material olefin obtained in Example 1;
  • Figure 5 is a H NMR spectrum of the raw material olefin obtained in Example 2.
  • Figure 6 is a 13 C NMR spectrum of the starting olefin obtained in Example 2.
  • Figure 8 is a 13 C NMR spectrum of the final product benzofuran derivative B obtained in Example 2;
  • the present invention synthesizes the benzofuran derivative A, comprising the following steps:
  • reaction formula is:
  • the purity of the crude product can be used in the next catalytic reaction without further purification. In this step, all operations must be carried out in a well-ventilated fume hood because cyanogen bromide is highly toxic and can generate hydrogen cyanide during the hydrolysis process.
  • reaction formula is:
  • the reaction flask was capped with a Teflon sealing cap and then taken out of the glove box; the reaction flask was heated to 90 ° C for 24 h; after the reaction was completed, it was cooled to room temperature and diluted with 10.0 ml of diethyl ether; by TLC thin layer chromatography
  • the reaction (1:4 EtOAc/hexanes) was used to complete the complete consumption of the reaction; the solution was concentrated with celite, and the product was purified by flash column chromatography (1:9 ⁇ 1:4 diethyl ether/hexane) to give product It was 147 mg of a yellow solid with a yield of 85%, which was the product benzofuran derivative A.
  • reaction formula is:
  • the purity of the crude product can be used in the next catalytic reaction without further purification. In this step, all operations must be carried out in a well-ventilated fume hood because cyanogen bromide is highly toxic and can generate hydrogen cyanide during the hydrolysis process.
  • reaction formula is:
  • Step 204 of the prepared 204 mg of olefin, 511 mg of non-metallic Lewis acid B (C 6 F 5 ) 3 and 5 mL of toluene were sequentially added to the reaction flask.
  • the reaction flask was capped with a Teflon sealing cap and then taken out of the glove box; the reaction flask was heated to 90 ° C for 24 h; after the reaction was completed, it was cooled to room temperature and diluted with 10.0 ml of diethyl ether; by TLC thin layer chromatography
  • the reaction (1:4 EtOAc/hexanes) was used to complete the complete consumption of the reaction; the solution was concentrated with celite, and the product was purified by flash column chromatography (1:9 ⁇ 1:4 diethyl ether/hexane). 177 mg of a red solid with a yield of 88% is the product benzofuran derivative B.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)

Abstract

L'invention concerne un procédé de synthèse d'un dérivé de benzofurane au moyen d'un acide de Lewis non métallique catalysant l'addition d'une liaison C-O à l'intérieur d'une molécule d'oléfine, comprenant les étapes suivantes : étape une, consistant à préparer une oléfine : à l'aide d'un dérivé de phénol en tant que matière première et réaliser trois étapes de réactions pour obtenir une oléfine qui agit en tant que substrat de réaction ; étape deux, consistant à ajouter un acide de Lewis non métallique et du toluène dans le substrat de réaction préparé à l'étape une pour obtenir un dérivé de benzofurane au moyen d'une réaction. La réaction utilise un acide de Lewis non métallique comme catalyseur pendant un processus de réaction, ce qui empêche un catalyseur métallique résiduel de contaminer un produit et permet d'éliminer également un post-traitement lourd.
PCT/CN2019/087153 2018-05-08 2019-05-16 Procédé de synthèse d'un dérivé de benzofurane au moyen d'un acide de lewis non métallique catalysant l'addition d'une liaison c-o à l'intérieur d'une molécule d'oléfine WO2019214749A1 (fr)

Applications Claiming Priority (2)

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CN201810429931.1 2018-05-08
CN201810429931.1A CN108530405A (zh) 2018-05-08 2018-05-08 非金属路易斯酸催化烯烃分子内加成c-o键合成苯并呋喃衍生物的方法

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WO2019214749A1 true WO2019214749A1 (fr) 2019-11-14

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Publication number Priority date Publication date Assignee Title
CN108530405A (zh) * 2018-05-08 2018-09-14 南京晓庄学院 非金属路易斯酸催化烯烃分子内加成c-o键合成苯并呋喃衍生物的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0345593A1 (fr) * 1988-06-10 1989-12-13 Takeda Chemical Industries, Ltd. Dérivés du coumarane substitués en position 2
WO2006000902A1 (fr) * 2004-06-25 2006-01-05 Pfizer Products Inc. Composes dihydrobenzofurane et leurs utilisations
CN102421767A (zh) * 2009-03-10 2012-04-18 武田药品工业株式会社 苯并呋喃衍生物
CN108530405A (zh) * 2018-05-08 2018-09-14 南京晓庄学院 非金属路易斯酸催化烯烃分子内加成c-o键合成苯并呋喃衍生物的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0345593A1 (fr) * 1988-06-10 1989-12-13 Takeda Chemical Industries, Ltd. Dérivés du coumarane substitués en position 2
WO2006000902A1 (fr) * 2004-06-25 2006-01-05 Pfizer Products Inc. Composes dihydrobenzofurane et leurs utilisations
CN102421767A (zh) * 2009-03-10 2012-04-18 武田药品工业株式会社 苯并呋喃衍生物
CN108530405A (zh) * 2018-05-08 2018-09-14 南京晓庄学院 非金属路易斯酸催化烯烃分子内加成c-o键合成苯并呋喃衍生物的方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KOESTER, DENNIS C. ET AL.: "Intramolecular Oxycyanation of Alkenes by Coope- rative Pd/BPh3 Catalysis", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 134, no. 15, 1 April 2012 (2012-04-01), pages 6544 - 6547, XP055651416, DOI: 10.1021/ja301375c *
NICOLAI, STEFANO ET AL.: "Pd-Catalyzed Intramolecular Oxyalkynylation of Alkenes with Hypervalent Iodine", ORGANIC LETTERS, vol. 12, no. 2, 10 December 2009 (2009-12-10), pages 384 - 387, XP055651422, DOI: 10.1021/ol9027286 *
ZHAO, JIYANG ET AL.: "An insight into the Lewis acid-catalyzed intramoleculai aminocyanation and oxycyanation of alkenes: a concerted or stepwise mechani- sm", CHEMICAL COMMUNICATIONS, vol. 51, 27 August 2015 (2015-08-27), pages 15450 - 15453, XP055651447, DOI: 10.1039/C5CC06808H *

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